Apremilast

Apremilast is a small-molecule inhibitor of phosphodiesterase 4 (PDE4), an enzyme involved in inflammatory signaling, and is primarily used to treat moderate to severe plaque psoriasis (in adults and children aged 6 years and older weighing at least 20 kg who are candidates for phototherapy or systemic therapy), active psoriatic arthritis, and oral ulcers associated with Behçet's disease in adults.^[1]^[2] Sold under the brand name Otezla, it is administered orally as tablets and was first approved by the U.S. Food and Drug Administration (FDA) in 2014 as a targeted therapy for these conditions, offering a non-biologic alternative to systemic treatments like methotrexate or biologics.^[1]^[3] By selectively inhibiting PDE4, apremilast elevates intracellular cyclic adenosine monophosphate (cAMP) levels, which suppresses the production of pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α) and interleukin-23 (IL-23), thereby reducing inflammation without broadly immunosuppressing the immune system.^[1]^[3] Apremilast's development by Celgene and acquisition by Amgen in 2019 marked it as the first FDA-approved oral PDE4 inhibitor for dermatologic and rheumatologic indications, with clinical trials demonstrating efficacy in reducing psoriatic lesions, joint symptoms, and oral ulcer frequency, though it is contraindicated in cases of known hypersensitivity.^[4]^[5]^[3] As of the 2024 updates to its labeling, apremilast remains a key option for patients seeking oral therapy without the need for injections.^[1]^[2]

Therapeutic applications

Approved indications

Apremilast, marketed as Otezla, received U.S. Food and Drug Administration (FDA) approval on March 21, 2014, for the treatment of adult patients with active psoriatic arthritis (PsA) who have had an inadequate response or intolerance to prior disease-modifying antirheumatic drug (DMARD) therapy.^[6] This indication targets patients with moderate to severe disease manifestations, including joint inflammation, enthesitis, and dactylitis, where prior treatments such as methotrexate or biologics have failed.^[7] On September 23, 2014, the FDA expanded approval to include adult patients with plaque psoriasis (PsO) (regardless of severity) who are candidates for phototherapy or systemic therapy.^[8] This was further expanded on December 20, 2021, to explicitly cover patients across all severities, including mild disease, based on the ADVANCE trial demonstrating efficacy in mild-to-moderate cases.^[1]^[9] Patient selection includes those who are candidates for phototherapy or systemic therapy, such as individuals with inadequate response to topical therapies, contraindications to other options, or those across severities including mild disease (PASI <10%).^[1] On April 25, 2024, the FDA approved apremilast for the treatment of moderate to severe plaque psoriasis in pediatric patients 6 years of age and older who are candidates for systemic therapy or phototherapy.^[10] This indication is for children weighing at least 20 kg with significant body surface area involvement and inadequate response to topical treatments or phototherapy.^[1] The FDA further approved apremilast on July 19, 2019, for the treatment of oral ulcers associated with Behçet's disease in adults.^[11] This indication applies to patients with recurrent oral ulcers who are candidates for systemic therapy, often those with moderate to severe disease activity despite topical treatments.^[7] In the European Union, the European Medicines Agency (EMA) granted marketing authorization for apremilast on January 15, 2015, for active PsA in adults with inadequate response or intolerance to prior DMARDs, and for moderate-to-severe chronic plaque PsO in adults who failed to respond to or have contraindications to at least one systemic therapy.^[12] The EMA approved the indication for oral ulcers in Behçet's disease on April 8, 2020, mirroring the FDA's focus on adults requiring systemic treatment for recurrent ulcers.^[13] The EMA also authorizes apremilast for the treatment of moderate to severe plaque psoriasis in children and adolescents from the age of 6 years and weighing at least 20 kg who are candidates for systemic therapy.^[14] Efficacy in PsA was demonstrated in the phase 3 PALACE trials, where apremilast 30 mg twice daily achieved American College of Rheumatology 20 (ACR20) response rates of approximately 38-40% at week 16, compared to 19% with placebo, in patients with active disease despite prior therapies.^[15] For PsO, the phase 3 ESTEEM trials showed PASI-75 response rates of about 33% at week 16 with apremilast 30 mg twice daily versus 6% with placebo, among adults with moderate-to-severe plaques eligible for systemic or phototherapy.^[16] The ADVANCE trials supported the expansion to mild-to-moderate PsO in adults.^[1] In Behçet's disease, the phase 3 RELIEF trial supported approval by showing significant reductions in oral ulcer frequency and pain in adults with active ulcers unresponsive to topical therapy.^[17]

Dosage and administration

Apremilast is administered orally as tablets for the treatment of conditions such as psoriatic arthritis (PsA), plaque psoriasis (PsO), and oral ulcers in Behçet's disease.^[7] The recommended maintenance dosage for adults is 30 mg twice daily, taken approximately 12 hours apart, following an initial titration period to minimize gastrointestinal adverse effects like nausea.^[7]^[18] To achieve the maintenance dose, apremilast requires a 5-day titration schedule as outlined in the following table:

Day	Morning Dose	Evening Dose
1	10 mg	None
2	10 mg	10 mg
3	10 mg	20 mg
4	20 mg	20 mg
5	20 mg	30 mg
6 and thereafter	30 mg	30 mg

The tablets should be swallowed whole and can be taken with or without food; no specific monitoring beyond routine clinical assessment is required during administration.^[7]^[18] For pediatric patients with plaque psoriasis aged 6 years and older weighing at least 20 kg, the recommended maintenance dosage is weight-based: 20 mg twice daily for body weight of 20 kg to less than 50 kg, and 30 mg twice daily for body weight of 50 kg or more, following the same 5-day titration schedule adjusted for the target dose (e.g., titrate to 10 mg/20 mg for lower weight).^[1]^[12] For patients with severe renal impairment (creatinine clearance <30 mL/min), the maintenance dose is reduced to 30 mg once daily, with titration using only the morning doses from the schedule above, omitting evening doses.^[7] No dosage adjustment is necessary for patients with hepatic impairment or for elderly patients, though the latter should be monitored for potential complications from gastrointestinal symptoms. For pediatric patients with renal impairment, dose adjustments follow adult guidelines based on severity.^[7]^[18] Discontinuation of apremilast does not require gradual tapering, but patients should be monitored for possible symptom rebound, such as worsening of psoriasis.^[7]

Safety profile

Contraindications and precautions

Apremilast is contraindicated in patients with known hypersensitivity to the drug or any of its excipients, as hypersensitivity reactions including angioedema and anaphylaxis have been reported.^[19] In pregnancy, animal reproduction studies have shown risks including dose-related increases in fetal loss and embryo-fetal death; available human data from postmarketing reports and clinical trials are limited and do not conclusively show an increased risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. It should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Females of reproductive potential are advised to use effective contraception during treatment to prevent pregnancy. Pregnant women exposed to apremilast are encouraged to enroll in a pregnancy exposure registry: 1-877-311-8972 or https://mothertobaby.org/ongoing-study/otezla/.[](https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/205437s014lbl.pdf)[](https://www.drugs.com/pregnancy/apremilast.html)[](https://www.ema.europa.eu/en/documents/product-information/otezla-epar-product-information_en.pdf) It is unknown if apremilast is excreted in human milk, but it was detected in milk of lactating mice at levels similar to those in plasma. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for apremilast and any potential adverse effects on the breastfed infant.^[19]^[20] Patients with a history of depression or suicidal ideation require careful risk-benefit assessment prior to initiating apremilast, given its association with increased depression incidence. Monitoring for emergence or worsening of depression, suicidal thoughts, or mood changes is essential, with prompt discontinuation recommended if such symptoms occur; patients, caregivers, and families should be informed to report any changes to healthcare providers.^[19] Weight loss can occur with apremilast treatment, necessitating baseline and periodic monitoring, particularly in patients with low body mass index (BMI <20 kg/m²) who may be more vulnerable to clinically significant decreases. If unexplained or substantial weight loss is observed, further evaluation is warranted, and discontinuation should be considered to prevent complications.^[19] Apremilast has no or negligible effects on the ability to drive or operate machinery, though caution is advised if central nervous system side effects such as headache manifest, potentially impairing alertness.^[12] Pediatric use is approved for moderate-to-severe plaque psoriasis and active psoriatic arthritis in children aged 6 years and older weighing at least 20 kg, where safety and efficacy are established; it is not approved for Behçet's disease, children under 6 years, or those under 20 kg, with close monitoring of growth recommended. In geriatric patients (aged 65 years and older), no dosage adjustment is required, though data are limited and increased vigilance for dehydration or hypotension from gastrointestinal effects is advised due to higher susceptibility.^[19]

Adverse effects

The most common adverse effects of apremilast are gastrointestinal in nature, including diarrhea (17-20% incidence in clinical trials for plaque psoriasis and psoriatic arthritis), nausea (15-17%), vomiting (3-5%), and decreased appetite (2-3%).^[19]^[21] These effects typically occur within the first two weeks of treatment, often resolve within four weeks, and their incidence can be reduced through gradual dose titration.^[19] Other frequently reported adverse effects include headache (6-14%, encompassing tension headache in about 9%), upper respiratory tract infection (7-15%), and nasopharyngitis (2-14%).^[19]^[21] Psychiatric effects are less common, with depression occurring in 1-2% of patients and insomnia in about 2%; suicidal ideation or behavior is rare, affecting fewer than 0.1-0.2%.^[19] Weight loss is a notable effect, with a mean reduction of 1-2 kg observed in the first six months of treatment; approximately 10-12% of patients experience 5-10% body weight loss, and 5-10% lose more than 10% of their baseline weight.^[19]^[21] Serious adverse effects include severe diarrhea that may lead to dehydration and require hospitalization, hypersensitivity reactions such as rash or angioedema (reported in postmarketing experience), and a modestly increased risk of infections like upper respiratory tract infections, though apremilast does not carry the same immunosuppressive risks as biologic therapies.^[19] In long-term studies extending up to five years, weight loss may persist but stabilizes, and no increased risk of malignancies (incidence rate of 1.0 per 100 patient-years) or serious infections (1.1 per 100 patient-years) has been observed compared to expected rates.^[22] Discontinuation due to adverse effects occurs in 5-8% of patients, primarily driven by gastrointestinal events such as diarrhea and nausea.^[19]^[21]

Drug interactions

Apremilast is primarily metabolized by the cytochrome P450 enzyme CYP3A4, which forms the basis for its interactions with drugs that induce or inhibit this enzyme. Co-administration with strong CYP3A4 inducers, such as rifampin, carbamazepine, phenobarbital, or phenytoin, significantly reduces apremilast exposure; for example, rifampin decreases apremilast's area under the curve (AUC) by approximately 72% and maximum concentration (Cmax) by 43%, potentially leading to loss of efficacy. Therefore, concurrent use of strong CYP3A4 inducers with apremilast is not recommended.^[19]^[23] In contrast, strong CYP3A4 inhibitors like ketoconazole have a modest effect on apremilast pharmacokinetics, increasing AUC by about 36% and Cmax by 5%, which is not considered clinically significant, and no dose adjustment is required, though monitoring for adverse effects is advised. Apremilast does not significantly interact with substrates of CYP2C9 or CYP2C19, such as warfarin or phenytoin (beyond its role as an inducer).^[23]^[19] No clinically relevant pharmacokinetic interactions occur between apremilast and oral contraceptives containing ethinyl estradiol and norgestimate. Similarly, co-administration with methotrexate, a common immunosuppressant used in psoriatic arthritis and psoriasis, shows no significant pharmacokinetic effects on either drug, allowing safe concurrent use. However, due to apremilast's immunomodulatory action, caution is warranted when combining it with other immunosuppressants like biologics, as this may lead to additive immunosuppressive effects and increased infection risk in patients with psoriatic arthritis or psoriasis.^[19]^[24] Food does not affect apremilast's bioavailability, so it may be taken with or without meals. No interactions with laboratory tests have been reported.^[19]

Pharmacology

Mechanism of action

Apremilast is a selective inhibitor of phosphodiesterase 4 (PDE4), particularly the PDE4D isoform, which prevents the hydrolysis of cyclic adenosine monophosphate (cAMP) to its inactive metabolite 5'-AMP.^[25] This inhibition leads to elevated intracellular cAMP levels in immune cells, thereby activating downstream signaling pathways including protein kinase A (PKA) and cAMP response element-binding protein (CREB)-mediated transcription.^[25] The resulting increase in cAMP suppresses pro-inflammatory signaling without broadly impairing immune function.^[3] The downstream effects of PDE4 inhibition by apremilast include reduced expression of key pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α), interleukin-23 (IL-23), interleukin-17 (IL-17), and interleukin-8 (IL-8). These reductions occur in relevant immune cells, including Th17 cells, monocytes, and keratinocytes, thereby modulating both innate and adaptive immune responses.^[25] In the context of plaque psoriasis (PsO) and psoriatic arthritis (PsA), this targeted action on PDE4 in skin and joint tissues dampens localized inflammation while avoiding widespread immunosuppression associated with broader therapies.^[3] Apremilast's selectivity for PDE4 isoforms minimizes off-target effects on other phosphodiesterase families, such as PDE3, which are implicated in cardiac and vascular adverse events observed with non-selective inhibitors like theophylline.^[26] In Behçet's disease, apremilast exerts similar anti-inflammatory effects by inhibiting PDE4 in neutrophils, reducing their activation, reactive oxygen species production, and neutrophil extracellular trap formation, which contributes to decreased oral ulcer inflammation.^[27] This mechanism supports its application in approved indications like PsO, PsA, and oral ulcers in Behçet's disease.^[3]

Pharmacokinetics

Apremilast is rapidly absorbed after oral administration, with a median time to maximum plasma concentration (Tmax) of approximately 2.5 hours. The absolute oral bioavailability is about 73%, and the pharmacokinetics are linear over the therapeutic dose range of 10 to 50 mg, with area under the curve (AUC) and maximum concentration (Cmax) increasing proportionally with dose. Food does not significantly affect the extent of absorption, although it may slightly delay Tmax.^[28] The apparent volume of distribution is 87 L, indicating distribution into extravascular tissues. Apremilast is approximately 68% bound to plasma proteins, primarily albumin. In animal models, apremilast crosses the placenta, with fetal-to-maternal plasma concentration ratios of 0.3 to 0.4 observed in monkeys.^[1] Metabolism of apremilast occurs primarily in the liver through multiple pathways, with cytochrome P450 (CYP) 3A4 mediating the major route of oxidative metabolism, and minor contributions from CYP1A2 and CYP2A6. The drug undergoes O-demethylation, followed by glucuronidation to form inactive metabolites, including the primary circulating metabolite M12 (O-desmethyl apremilast glucuronide), which accounts for about 39% of plasma radioactivity. Overall, 23 metabolites have been identified, with only 3% to 7% of the dose excreted unchanged.^[29]^[28] Elimination of apremilast follows a half-life of 6 to 9 hours, with plasma clearance of approximately 10 L/h. Following oral administration of radiolabeled apremilast, approximately 58% of the total radioactivity is recovered in urine and 39% in feces, predominantly as metabolites. Steady-state plasma concentrations are achieved within 4 to 5 days of twice-daily (BID) dosing, with minimal accumulation (about 1.6-fold) due to the elimination half-life.^[28]^[29]^[30] In special populations, apremilast clearance is reduced in patients with severe renal impairment (creatinine clearance <30 mL/min), resulting in an 88% increase in AUC and a 47% decrease in clearance, necessitating a dosage adjustment to 30 mg once daily. The pharmacokinetics of apremilast are not affected by moderate or severe hepatic impairment (Child-Pugh B or C). No dosage adjustment is necessary for patients with any degree of hepatic impairment, and pharmacokinetics are similar across age, gender, and race.^[28]^[18]

Chemistry

Chemical structure

Apremilast possesses the IUPAC name (S)-N-{2-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}acetamide. Its molecular formula is C22H24N2O7S, corresponding to a molecular weight of 460.50 g/mol. The core structure of apremilast consists of a phthalimide ring substituted at the 4-position with an acetamido (-NHCOCH3) group and at the imide nitrogen with a chiral 1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl side chain.^[31] This side chain includes a 3-ethoxy-4-methoxyphenyl moiety linked via a β-(methylsulfonyl)ethyl bridge to the phthalimide, contributing to its overall identity and potential for targeted binding interactions. Apremilast is structurally related to thalidomide analogs through its phthalimide core but lacks the glutarimide ring associated with teratogenicity in thalidomide.^[32] Apremilast features a single chiral center at the α-carbon of the ethyl linker adjacent to the phthalimide nitrogen, with the (S)-enantiomer being the pharmacologically active form. Enantioselective synthesis is required to isolate this active (S)-configuration, ensuring the compound's specificity and efficacy.^[33] For reference, the canonical SMILES notation is CCOC1=C(C=CC(=C1)C@@HN2C(=O)C3=C(C2=O)C(=CC=C3)NC(=O)C)OC.

Physical and chemical properties

Apremilast appears as a white to pale yellow powder.^[7]^[34] It is a crystalline solid with a melting point of 152–156 °C.^[35]^[36] The compound exhibits low aqueous solubility, with values ranging from 10.8 to 14.5 µg/mL across pH 1 to 8, rendering it poorly soluble in water (<0.1 mg/mL).^[37] It shows higher solubility in organic solvents, such as >80 mg/mL in DMSO and approximately 3 mg/mL in ethanol.^[38]^[39] The pKa is approximately 12.58, consistent with its non-ionizable nature under physiological conditions.^[40] Its octanol-water partition coefficient (LogP) is about 1.8, indicating moderate lipophilicity that supports oral bioavailability.^[40]^[36] Apremilast is stable under standard storage conditions at room temperature (below 30 °C), protected from light and moisture.^[7] It undergoes degradation primarily through hydrolysis in acidic environments, with significant breakdown observed after exposure to 0.1 N HCl for several hours.^[41]^[42] In pharmaceutical formulations, apremilast is available as film-coated tablets in 10 mg (pink), 20 mg (brown), and 30 mg (beige) strengths, incorporating excipients such as lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, and magnesium stearate in the core, along with polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc, and iron oxides in the coating.^[7] Multiple polymorphic forms (A–G) have been identified, with Form B serving as the stable anhydrous commercial form.^[37]

History

Development and discovery

Apremilast was discovered by Celgene Corporation in the early 2000s as part of a phosphodiesterase 4 (PDE4) inhibitor program that evolved from thalidomide derivatives, specifically phthalimide-based immunomodulatory compounds aimed at modulating inflammatory cytokines.^[43] The compound, chemically known as (S)-N-[2-[1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonylethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]acetamide, emerged from efforts to optimize earlier analogs like 3-(1,3-dioxo-1,3-dihydroisoindol-2-yl)-3-(3,4-dimethoxyphenyl)propionic acid for enhanced PDE4 potency and reduced gastrointestinal side effects. Initial synthesis of apremilast occurred around 2002–2003, with the compound identified for its improved selectivity as a PDE4 inhibitor compared to earlier agents like roflumilast, particularly due to a lower propensity to induce emesis in preclinical models such as ferrets (no emetic episodes at 1 mg/kg orally).^[43] In vitro assays demonstrated an IC50 of approximately 74 nM for PDE4 inhibition in U937 human monocytic cells, alongside suppression of tumor necrosis factor-alpha (TNF-α) production.^[44] Preclinical studies confirmed apremilast's efficacy in animal models of inflammation, including reduced epidermal thickness and keratinocyte proliferation in a human NK cell-driven SCID mouse model of psoriasis (at 5 mg/kg/day) and amelioration of joint swelling and histological damage in mouse collagen-induced arthritis and mAb/LPS-induced models.^[44]^[45] Safety evaluations showed promising profiles, with no-observed-adverse-effect levels (NOAELs) of 10 mg/kg/day in rodents (6-month studies, despite arteritis at higher doses) and 600 mg/kg/day in primates (12-month studies, with minimal toxicity).^[44] The development rationale centered on PDE4 inhibition to elevate intracellular cyclic AMP levels, thereby modulating multiple pro- and anti-inflammatory mediators (e.g., reducing TNF-α while increasing IL-10) without the infection risks associated with direct TNF-α biologic inhibitors, positioning apremilast as a first-in-class oral small molecule for psoriatic arthritis (PsA) and psoriasis (PsO).^[44] Celgene filed a patent application (US 7,427,638) on March 19, 2003, covering the stereomerically pure composition of apremilast and its use in treating inflammatory disorders, which was granted on September 23, 2008.^[43] Following these preclinical findings, Celgene submitted an Investigational New Drug (IND) application to the FDA in 2007, enabling the transition to human clinical evaluation based on the compound's favorable efficacy and safety data in rodents and non-human primates.^[46]

Clinical trials and approvals

The pivotal phase 3 PALACE 1, 2, and 3 trials, conducted between 2010 and 2013, evaluated apremilast in adults with active psoriatic arthritis (PsA) despite conventional therapy, enrolling over 1,000 patients across the studies.^[47] In each trial, apremilast 30 mg twice daily met the primary endpoint of American College of Rheumatology 20 (ACR20) response at week 16, achieving rates of 38% compared to 19% with placebo, with sustained benefits observed in long-term extensions up to 5 years, including continued ACR20 responses and improvements in enthesitis and dactylitis.^[48]^[49] The phase 3 ESTEEM 1 and 2 trials, also spanning 2010 to 2013, assessed apremilast in over 1,200 adults with moderate to severe plaque psoriasis (PsO), focusing on scalp, nail, and palmoplantar involvement in addition to body surface area.^[50] Apremilast 30 mg twice daily demonstrated significant efficacy at week 16, with 33% of patients achieving a 75% improvement in Psoriasis Area and Severity Index (PASI-75) versus 6% on placebo, and 20% attaining a static Physician Global Assessment (sPGA) score of 0 or 1, with responses maintained through 52 weeks in ongoing treatment arms.^[51] For Behçet's syndrome, the phase 3 RELIEF trial from 2016 to 2018 randomized approximately 400 adults with active oral ulcers to apremilast 30 mg twice daily or placebo.^[52] The primary endpoint was met, with apremilast reducing the median number of oral ulcer days by 38% compared to placebo over weeks 1 to 12 (3.2 versus 5.2 days), alongside decreases in ulcer pain and number, and benefits sustained up to 52 weeks in the open-label extension.^[53] Apremilast received U.S. Food and Drug Administration (FDA) approval on March 21, 2014, for the treatment of active PsA and moderate to severe PsO in adults.^[7] The FDA expanded approval on July 19, 2019, to include oral ulcers associated with Behçet's disease in adults.^[10] Further expansions occurred on April 25, 2024, for moderate to severe plaque psoriasis in pediatric patients 6 years of age and older weighing at least 20 kg, and in July 2025 for active psoriatic arthritis in pediatric patients 6 years of age and older weighing at least 50 kg.^[54]^[55] In the European Union, the European Medicines Agency (EMA) granted marketing authorization for apremilast on January 15, 2015, for PsA and PsO, with an extension for Behçet's oral ulcers approved in 2020.^[14] In August 2023, Bristol Myers Squibb sold the rights to apremilast (Otezla) to Amgen for $13.4 billion, following BMS's 2019 acquisition of Celgene.^[56] Post-marketing surveillance has informed label updates, including a 2025 revision (s014) incorporating long-term safety data from integrated analyses of trials and real-world use, confirming no new safety signals beyond known profiles.^[19]^[57] Across these trials, limitations included higher gastrointestinal adverse events leading to discontinuation rates of 10-15% for apremilast versus 5% for placebo, primarily due to nausea and diarrhea.^[58] Additionally, while effective as monotherapy or in combination, apremilast showed inferior efficacy to biologic therapies in indirect comparisons and network meta-analyses for achieving higher response thresholds in PsA and PsO.^[59]^[60]

Society and culture

Brand names and availability

Apremilast is primarily marketed under the brand name Otezla by Amgen, following the company's acquisition of the drug from Celgene (which had been acquired by Bristol-Myers Squibb) in November 2019.^[61] No other widely used brand names exist globally, and generic versions remain unavailable in most markets as of 2025 due to ongoing patent protections; in the United States, for instance, court rulings have delayed generic entry until at least February 2028.^[62] Limited generic equivalents, such as pms-APREMILAST and Pr JAMP Apremilast, are available only in Canada.^[63]^[64] Otezla is approved for use in more than 70 countries worldwide, including the United States (since 2014), the European Union (since 2015), Canada, Japan (since 2016), and Australia (since 2015).^[65]^[14]^[66] The drug is formulated as oral tablets in strengths of 10 mg, 20 mg, and 30 mg, with starter packs available to facilitate dose titration over the initial 5 to 14 days of treatment, typically containing a combination of these strengths (e.g., 4 tablets each of 10 mg and 20 mg, plus 30 mg tablets for maintenance).^[7]^[67] Distribution is restricted to prescription-only access, with handling often through specialty pharmacies in regions like the United States due to the drug's cost and specialized logistics; these pharmacies deliver directly to patients via mail.^[68] No supply shortages for apremilast have been reported in 2025, supported by steady production and increasing sales volumes under Amgen's management.^[69]

Legal status

In the United States, apremilast is classified as a prescription-only medication approved by the Food and Drug Administration (FDA) and is not a controlled substance under the Drug Enforcement Administration (DEA) schedules, as it is non-narcotic.^[19] No Risk Evaluation and Mitigation Strategy (REMS) program is required for its distribution, though prescribers must counsel patients on the associated risk of depression, including monitoring for worsening symptoms or suicidal ideation.^[19] In August 2024, the FDA expanded approval to include treatment of moderate to severe plaque psoriasis in pediatric patients aged 6 years and older who are candidates for systemic therapy or phototherapy.^[70] In the European Union, apremilast received centralized marketing authorization from the European Medicines Agency (EMA) in January 2015 and is available exclusively by prescription, with no designation as a controlled substance or special scheduling.^[14] Treatment initiation is recommended under specialist supervision for approved indications such as psoriasis and psoriatic arthritis.^[12] In October 2024, the EMA approved its use for moderate to severe plaque psoriasis in children and adolescents aged 6 years and older.^[71] Approval extends to select other regions, including authorization by Japan's Pharmaceuticals and Medical Devices Agency (PMDA) in December 2016 for psoriasis and psoriatic arthritis, and by Health Canada in November 2014 for plaque psoriasis (with subsequent expansions).^[72]^[73] However, apremilast lacks approval in many low- and middle-income countries and is not included on the World Health Organization's Model List of Essential Medicines as of the 2025 update.^[74] Off-label prescribing of apremilast is legally permissible in the United States and similar jurisdictions, where physicians have discretion to use FDA-approved drugs for unindicated conditions, though such use is discouraged absent robust clinical evidence.^[3] Apremilast remains protected by key patents, including U.S. Patent No. 6,962,940, set to expire in 2028, with pediatric exclusivity potentially extending market protection; as of November 2025, no generic versions have launched commercially despite some FDA tentative approvals, due to ongoing patent challenges.^[65]^[75] In 2025, the FDA issued an updated prescribing information label for apremilast to refine warnings on psychiatric effects like depression and suicidality, as well as gastrointestinal risks, without adding a black box warning.^[19]

Economics and access

In the United States, the list price for a 30-day supply of apremilast (30 mg twice daily) is approximately $5,324 as of 2025, though actual patient costs can vary based on insurance coverage and pharmacy pricing, often ranging from $5,000 to $6,000 per month without assistance.^[76] Amgen, the manufacturer, offers the Amgen SupportPlus Co-Pay Program, which can reduce out-of-pocket costs to as low as $0 for eligible commercially insured patients, covering copays up to program limits, and the Amgen Safety Net Foundation provides free medication for qualifying uninsured or underinsured individuals meeting income criteria.^[77]^[78] In the European Union, pricing for apremilast varies by country, influenced by national tender systems and confidential discounts. It is reimbursed in most EU countries for approved indications such as moderate-to-severe plaque psoriasis and active psoriatic arthritis, typically requiring prior authorization to confirm patient eligibility based on disease severity and prior treatment failures.^[14] Globally, the high cost of apremilast creates significant access barriers in low- and middle-income countries, where it is often unavailable or unaffordable due to limited reimbursement and distribution networks, exacerbating treatment disparities for psoriasis and psoriatic arthritis patients. Generic versions are available in Canada but delayed in the US until at least 2028 due to ongoing patent protections, with full generic entry potentially not occurring until after 2034 in some markets.^[79] Amgen has general initiatives to improve medicine access in low- and middle-income countries through partnerships and tiered pricing, though apremilast is not WHO-prequalified, limiting its inclusion in essential medicines programs.^[80] Apremilast faces competition from lower-cost options like methotrexate and emerging JAK inhibitors. Economic analyses indicate favorable cost-effectiveness compared to biologics, particularly beneficial for patients ineligible for biologics.^[81]

Research and future directions

Ongoing studies

The completed PALACE 1-4 open-label extension (OLE) studies, which followed patients from the initial phase 3 trials, provided over 5 years of cumulative data demonstrating maintained American College of Rheumatology (ACR) 20 responses in approximately 50% of PsA patients receiving continuous apremilast 30 mg twice daily.^[82]^[83] These extensions highlight stable improvements in joint symptoms, physical function, and psoriasis severity without new safety signals emerging beyond the initial treatment periods.^[84] Phase 4 studies are evaluating apremilast in combination with methotrexate (MTX) or biologics for refractory PsA, focusing on safety and tolerability in real-world settings. For instance, observational and interventional trials assess additive effects and adverse event profiles when apremilast is added to tumor necrosis factor inhibitors or interleukin-17 antagonists in patients with inadequate responses to monotherapy.^[85] Pediatric investigations include a phase 3 trial (NCT04804553) examining apremilast in children aged 2-17 years with active juvenile PsA, which is ongoing as of 2025.^[86] This study addresses unmet needs in younger populations, following the 2024 FDA approval of apremilast for pediatric plaque psoriasis in children aged 6 and older.^[70] Safety registries, such as the CorEvitas PsO/PsA cohorts initiated in 2020 and ongoing through 2025, monitor real-world adverse events, including weight loss observed in up to 12% of apremilast-treated individuals, alongside tracking of infections and discontinuations.^[87]^[88] Post-2020 analyses indicate no increased risk of COVID-19 infection or severe outcomes with apremilast use in psoriasis and PsA patients compared to placebo or other therapies.^[89]^[90] As of November 2025, ClinicalTrials.gov lists approximately 20 active trials for apremilast, predominantly observational studies tracking long-term outcomes, with additional interventional efforts in combination regimens and special populations.

Potential new indications

Apremilast has shown preliminary promise in phase 2 trials for atopic dermatitis (AD), particularly in moderate cases, where a 2019 randomized, placebo-controlled study demonstrated that the 40 mg twice-daily dose achieved an EASI-75 response in approximately 33% of patients compared to 18% on placebo, though statistical significance was not reached (p=0.067).^[91] This modest efficacy aligns with reduced atopic dermatitis-related biomarkers, suggesting potential synergy with anti-IL-13 therapies in Th2-driven inflammation, as explored in case reports of recalcitrant AD.^[92] However, the 30 mg dose failed to show significant EASI improvements, highlighting dose-dependent limitations in broader AD applications.^[91] In hidradenitis suppurativa (HS), open-label phase 2 studies have reported encouraging interim results for mild-to-moderate disease, with one 2019 trial (n=20) showing 65% of participants achieving significant improvements in disease activity scores after 16 weeks of 30 mg twice daily.^[93] Another small cohort (n=15) noted a 53.3% clinical response rate, including a 25% reduction in abscess and nodule counts, particularly beneficial for Hurley stage II patients.^[92] These findings position apremilast as a potential oral option for HS management, though larger controlled trials are needed to confirm durability.^[94] Emerging evidence from a 2025 narrative review supports apremilast's exploration in other immune-mediated skin disorders, such as pyoderma gangrenosum and lichen planus, where small open-label studies (n<50) reported response rates of 40-60% based on physician global assessment improvements.^[92] For pyoderma gangrenosum, a 2022 case series demonstrated lesion resolution with monotherapy in refractory cases, while lichen planus pilot studies showed 30-35% of patients achieving at least a 2-grade PGA reduction at 12 weeks.^[92] These applications leverage apremilast's PDE4 inhibition in Th17-mediated pathways, but data remain limited to uncontrolled settings.^[92] Systemically, early phase 2 data for axial spondyloarthritis indicate limited efficacy, with ASAS40 responses around 25% in a small 12-week trial (n=38), failing to outperform placebo significantly and suggesting insufficient impact on axial symptoms.^[95] Interest in inflammatory bowel disease (IBD) has waned due to apremilast's prominent gastrointestinal side effects, including diarrhea and nausea in up to 40% of users, which exacerbate IBD symptoms and limit tolerability.^[3] A 2025 meta-analysis of immune-mediated diseases reinforces apremilast's niche role in mild-to-moderate cases, with higher failure rates in severe presentations across dermatologic and rheumatologic contexts.^[96] As of November 2025, no phase 3 trials have been initiated for these new indications, with research emphasis remaining on dermatologic expansions rather than systemic approvals.^[92]